Cholesterol is necessary for all cells to function. The intracellular cholesterol transporters Npc1 and Npc2 control sterol trafficking and their malfunction leads to Neimann–Pick Type C disease, a rare disorder affecting the nervous system and the intestine. Unlike humans that encode single Npc1 and Npc2 transporters, flies encompass two Npc1 (Npc1a-1b) and eight Npc2 (Npc2a-2h) members, and most of the
Npc2 family genes remain unexplored. Here, we focus on the intestinal function of
Npc2c in the adult. We find that
Npc2c is necessary for intestinal stem cell (ISC) mitosis, maintenance of the ISC lineage, survival upon pathogenic infection, as well as tumor growth. Impaired mitosis of
Npc2c-silenced midguts is accompanied by reduced expression of
Cyclin genes, and genes encoding ISC regulators, such as
Delta,
unpaired1 and
Socs36E. ISC-specific
Npc2c silencing induces
Attacin-
A expression, a phenotype reminiscent of Gram-negative bacteria overabundance. Metagenomic analysis of
Npc2c-depleted midguts indicates intestinal dysbiosis, whereby decreased commensal complexity is accompanied by increased gamma-proteobacteria. ISC-specific
Npc2c silencing also results in increased cholesterol aggregation. Interestingly, administration of the non-steroidal ecdysone receptor agonist, RH5849, rescues mitosis of
Npc2c-silenced midguts and increases expression of the ecdysone response gene
Broad, underscoring the role of
Npc2c and sterols in ecdysone signaling. Assessment of additional
Npc2 family members indicates potential redundant roles with
Npc2c in ISC control and response to ecdysone signaling. Our results highlight a previously unidentified essential role of
Npc2c in ISC mitosis, as well as an important role in ecdysone signaling and microbiome composition in the
Drosophila midgut.
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